CN101544647A - (4aR,8aR)-3a-(difluoromethyl)decahydro-1H-benzene[d]pyrrole[1,2-a]-thiazole-1-ketone and synthesis method thereof - Google Patents
(4aR,8aR)-3a-(difluoromethyl)decahydro-1H-benzene[d]pyrrole[1,2-a]-thiazole-1-ketone and synthesis method thereof Download PDFInfo
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- CN101544647A CN101544647A CN200910048349A CN200910048349A CN101544647A CN 101544647 A CN101544647 A CN 101544647A CN 200910048349 A CN200910048349 A CN 200910048349A CN 200910048349 A CN200910048349 A CN 200910048349A CN 101544647 A CN101544647 A CN 101544647A
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Abstract
The invention relates to (4aR,8aR)-3a-(difluoromethyl)decahydro-1H-benzene[d]pyrrole[1,2-a]-thiazole-1-ketone and a synthesis method thereof. The structural formula of the compound is shown as right. The method comprises the following steps: dissolving difluoro gamma-methyl keto ester and catalytic dosage of paratoluenesulfonic acid into toluene, adding catalytic dosage of anhydrous magnesium sulfate, stirring the mixture to reflux for 20 to 60 minutes, and then adding (1R,2R)-1,2- cyclohexanediamine; adding the catalytic dosage of paratoluenesulfonic acid after continuously reacting for 10 to 15 hours, wherein the mol ratio of the difluoro gamma-methyl keto ester to the (1R,2R)-1,2-cyclohexanediamine is (1-1.2):1; performing reflux reaction for 10 to 15 hours, and ending the reaction; and performing separation and purification to obtain a yellow sticky liquid, namely the (4aR,8aR)-3a-(difluoromethyl)decahydro-1H-benzene[d]pyrrole[1,2-a]-thiazole-1-ketone. In the invention, raw materials are easy to obtain, the operation is simple, the product is synthesized by a one-pot method, the productivity is high up to 82 percent, and the product is suitable to be produced on a large scale.
Description
Technical field:
The present invention relates to a kind ofly be (4aR, 8aR)-synthetic method of 3a-(difluoromethyl) decahydro-1H-benzo [d] pyrroles [1,2-a]-imidazoles-1-ketone.
Background technology:
Since the fluorine Lyons appearance of the '30s initial stage in last century, organic fluorine chemistry shows flourish trend always.Because the introducing of fluorine atom causes organic and mineral compound demonstrates unique physics, chemical property and physiologically active.Fluorochemicals has physiologically active and wide application prospect widely, and the synthetic method of this compounds and property of medicine research thereof have obtained very big attention.Its synthetic method is one of organic fluorine chemistry research direction always.
Heterogeneous ring compound is very wide in distributed in nature, and its quantity almost accounts for 1/3rd of known organic compound, and purposes is also a lot.Some of many important materials such as chlorophyll and clinical application have the natural drug of significant curative effect and synthetic drugs etc., all contain the structure of heterogeneous ring compound.And in the structure of these heterogeneous ring compounds, mostly contain nitrogen heteroatom.Synthetic and the application of fluorine-containing heterocycles has obtained further investigation especially, in a lot of marketed drug fluorine-containing heterocycle structure is arranged all.As antifungal drug fluconazole, antitumour drug Ro 2-9757 etc.
Document (Chimirri, A. were arranged in 1989; Sarro, A.D.; Sarro, G.D.; Grasso, S.; Trimarchi, G.R.J.Med.Chem.1989,32,93-95.) reported that benzoglyoxaline pyrrolones derivative has anti-epileptic, anticonvulsant biological activity, can be applicable in the medicine.There is phenyl ring the benzoglyoxaline pyrrolones derivative 3a position of being reported in this piece article, and on the phenyl ring electron-withdrawing group is arranged.
The synthetic method of this compound does not have report at present as yet.
Summary of the invention:
One of purpose of the present invention be to provide a kind of new compound (4aR, 8aR)-3a-(difluoromethyl) decahydro-1H-benzo [d] pyrroles [1,2-a]-imidazoles-1-ketone.
Two of purpose of the present invention is to provide the synthetic method of this compound.
For achieving the above object, the reaction mechanism that the inventive method has adopted is:
According to above-mentioned reaction mechanism, the present invention adopts following technical scheme:
A kind of (4aR, 8aR)-3a-(difluoromethyl) decahydro-1H-benzo [d] pyrroles [1,2-a]-imidazoles-1-ketone, it is characterized in that the structure of this compound is:
(4aR, 8aR)-3a-(difluoromethyl) decahydro-1H-benzo [d] pyrroles [1,2-a]-imidazoles-1-ketone
The physical parameter of this compound:
Molecular formula: C
7H
9F
3N
2O
Structural formula:
Chinese named: (4aR, 8aR)-3a-(difluoromethyl) decahydro-1H-benzo [d] pyrroles [1,2-a]-imidazoles-1-ketone
English name:
(4aR，8aR)-3a-(dif]uoromethyl)decahydro-1H-benzo[d]pyrrolo[1，2-a]imidazol-1-one
Molecular weight: 230.24
Outward appearance: yellow viscous liquid
Infrared spectra (adopting the Perkin-Elmer983G infrared spectrometer, liquid-film method):
νmax(cm
-1)：3302，2931，2871，1711，1456，1341，1227，706
Proton nmr spectra (500MHz, CDCl
3): 5.848,5.736,5.621 (t, J=56Hz, 1H, CF
2H); 2.979～2.824 (m, 3H, NH, CH, H-CH
2); 2.619～2.533 (m, 2H, CH
2); 2.410,2.388,2.378,2.358 (q, J=11Hz, 1H, CH); 2.023～1.983 (m, 1H, H-CH
2); 1.892～1.759 (m, 3H, CH
2, H-CH
2); 1.397～1.249 (m, 4H, CH
2, CH
2)
Nucleus magnetic resonance fluorine spectrum (470MHz, CDCl
3, interior mark: C
6F
6) :-125.47 ,-125.59 (d, J=56.4Hz, 0.84);-126.07 ,-126.19 (d, J=56.4Hz, 1);-133.76 ,-133.88 (d, J=56.4Hz, 1);-134.36 ,-134.48 (d, J=56.4Hz, 0.84)
Carbon-13 nmr spectra (125MHz, CDCl
3): 181.52; 116.31,114.33,112,36 (J=247.5Hz); 85.24,85.04,84.85 (J=25Hz); 66.53; 64.61; 34.91; 30.98; 29.85; 29.65; 24.62; 24.48
A kind of synthetic above-mentioned (4aR, 8aR)-3a-(difluoromethyl) decahydro-1H-benzo [d] pyrroles [1,2-a]-method of imidazoles-1-ketone, it is characterized in that this method has following steps: difluoro gamma-keto acid ethyl ester and catalytic dosage of paratoluenesulfonic acid are dissolved in the toluene, the anhydrous magnesium sulfate that adds catalyst levels again, add after refluxing 20～60 minutes under stirring (1R, 2R)-1, the 2-cyclohexanediamine; React after 10～15 hours catalytic dosage of paratoluenesulfonic acid again; Described difluoro gamma-keto acid ethyl ester and (1R, 2R)-1, the mol ratio of 2-cyclohexanediamine is: (1～1.2): 1; Back flow reaction 10～15 hours, reaction finishes; Separation and purification gets yellow viscous liquid, be (4aR, 8aR)-3a-(difluoromethyl) decahydro-1H-benzo [d] pyrroles [1,2-a]-imidazoles-1-ketone.
In the pharmaceutical chemistry field, fluorine atom or one contain fluoroalkyl and are incorporated into and are considered to one of most effectual way that host compound is modified in the host molecule.Because the fluorine atom radius is little, has bigger electronegativity again, its formed C-F key bond energy is than big many of C-H key bond energy, the stability and the physiologically active of organofluorine compound have been increased significantly, fluorinated organic compound also has higher fat-soluble and hydrophobicity in addition, promote it to absorb in vivo and transmission speed, physiological action is changed.Have characteristics such as consumption is few, toxicity is low, drug effect is high, metabolic capacity is strong so a lot of fluorine-containing medicines and agricultural chemicals are relative on performance, this makes its proportion in the new pharmaceutical pesticide species more and more higher.The invention the benzoglyoxaline ring is carried out structural modification, the phenyl ring of benzoglyoxaline ring is reduced, and the fluoro-containing group difluoromethyl with electrophilic function is incorporated into the 3a position of decahydro benzoglyoxaline pyrrolidone analog derivative, replace the phenyl ring that has the electrophilic function originally, make (4aR of the present invention, 8aR)-and 3a-(difluoromethyl) decahydro-1H-benzo [d] pyrroles [1,2-a]-imidazoles-1-ketone should have stronger activity, more helps absorbing.And products therefrom Stability Analysis of Structures of the present invention, physiologically active be stronger, be easy to absorb.
The present invention has following conspicuous high-lighting characteristics and significance advantage: raw material of the present invention is easy to get, and operates very simply, and one kettle way is synthetic, and productive rate 82% is fit to scale operation.
Embodiment:
Embodiment one: preparation (4aR, 8aR)-3a-(difluoromethyl) decahydro-1H-benzo [d] pyrroles [1,2-a]-imidazoles-1-ketone employing following steps: 1. in 50 milliliters the round-bottomed flask that reflux condensing tube is housed, add difluoro gamma-keto acid ethyl ester 0.40 gram, p-methyl benzenesulfonic acid 0.019 gram, 25 milliliters of toluene, anhydrous magnesium sulfate 0.2 gram.Said mixture stirring and refluxing in oil bath add after half an hour (1R, 2R)-1,2-cyclohexanediamine 0.228 gram; 2. reactant reaction solution yellowing gradually under refluxing.React and add 0.019 gram p-methyl benzenesulfonic acid after 12 hours again.Continue reaction 12 hours, then stopped reaction.Suction filtration was removed anhydrous magnesium sulfate after reaction finished, and filtrate concentrates.3. the concentrated solution that obtains is separated with silica gel column chromatography, developping agent is that volume ratio is the sherwood oil of 6:1 and the mixed solvent of ethyl acetate, gets yellow viscous liquid 0.38 gram, and productive rate is 82%.
Embodiment two: preparation (4aR, 8aR)-3a-(difluoromethyl) decahydro-1H-benzo [d] pyrroles [1,2-a]-imidazoles-1-ketone employing following steps: 1. in 250 milliliters the round-bottomed flask that reflux condensing tube is housed, add difluoro gamma-keto acid ethyl ester 10 grams, p-methyl benzenesulfonic acid 0.475 gram, 150 milliliters of toluene, anhydrous magnesium sulfate 5 grams.Said mixture stirring and refluxing in oil bath add after half an hour (1R, 2R)-1,2-cyclohexanediamine 5.7 gram; 2. reactant reaction solution yellowing gradually under refluxing.React and add 0.475 gram p-methyl benzenesulfonic acid after 12 hours again.Continue reaction 16 hours, then stopped reaction.Suction filtration was removed anhydrous magnesium sulfate, concentrated filtrate after reaction finished.3. the concentrated solution that obtains is separated with silica gel column chromatography, developping agent is that volume ratio is the sherwood oil of 6:1 and the mixed solvent of ethyl acetate, gets yellow viscous liquid 9.2 grams, and productive rate is 80%.
Embodiment three: preparation (4aR, 8aR)-3a-(difluoromethyl) decahydro-1H-benzo [d] pyrroles [1,2-a]-imidazoles-1-ketone employing following steps: 1. in 2 liters the round-bottomed flask that reflux condensing tube is housed, add difluoro gamma-keto acid ethyl ester 100 grams, p-methyl benzenesulfonic acid 4.75 grams, 1000 milliliters of toluene, anhydrous magnesium sulfate 20 grams.Said mixture stirring and refluxing in oil bath adds after half an hour that (1R, 2R)-1,2. 2-cyclohexanediamine 57 restrains reactant reaction solution yellowing gradually under refluxing.React and add 4.75 gram p-methyl benzenesulfonic acids after 12 hours again.Continue reaction 20 hours, then stopped reaction.Suction filtration was removed anhydrous magnesium sulfate, concentrated filtrate after reaction finished.3. the concentrated solution that obtains is separated with silica gel column chromatography, developping agent is that volume ratio is the sherwood oil of 6:1 and the mixed solvent of ethyl acetate, gets yellow viscous liquid 89.7 grams, and productive rate is 78%.
Claims (2)
1. one kind (4aR, 8aR)-3a-(difluoromethyl) decahydro-1H-benzo [d] pyrroles [1,2-a]-imidazoles-1-ketone and synthetic method thereof, it is characterized in that the structure of this compound is:
2. one kind is synthesized (4aR according to claim 1,8aR)-3a-(difluoromethyl) decahydro-1H-benzo [d] pyrroles [1,2-a]-method of imidazoles-1-ketone, it is characterized in that this method has following steps: difluoro gamma-keto acid ethyl ester and catalytic dosage of paratoluenesulfonic acid are dissolved in the toluene, the anhydrous magnesium sulfate that adds catalyst levels again, add after refluxing 20～60 minutes under stirring (1R, 2R)-1, the 2-cyclohexanediamine; React after 10～15 hours catalytic dosage of paratoluenesulfonic acid again; Described difluoro gamma-keto acid ethyl ester and (1R, 2R)-1, the mol ratio of 2-cyclohexanediamine is: (1～1.2): 1; Back flow reaction 10～15 hours, reaction finishes; Separation and purification gets yellow viscous liquid, be (4aR, 8aR)-3a-(difluoromethyl) decahydro-1H-benzo [d] pyrroles [1,2-a]-imidazoles-1-ketone.
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| CN200910048349A CN101544647A (en) | 2009-03-26 | 2009-03-26 | (4aR,8aR)-3a-(difluoromethyl)decahydro-1H-benzene[d]pyrrole[1,2-a]-thiazole-1-ketone and synthesis method thereof |
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Application publication date: 20090930 |